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Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 74486

Special Issue Editor

Prof. Dr. Changjong Moon

E-Mail
Guest Editor
College of Veterinary Medicine, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea
Interests: behavioral neuroscience; cognitive function; emotional regulation; prefrontal cortex; hippocampus; molecular neurobiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Various animal models have played a key role in neurological disorder research. The models aim to replicate various aspects of the disorders, including the genetic basis, histopathological lesions, and clinical symptoms. They provide us with improved comprehension of the etiopathogenesis, with a final goal of mechanistically constructed therapeutics which eventually lead to the modification and/or prevention of neurological disorders. Despite the vast amount of knowledge previously assimilated, researchers and the general public can still benefit from novel animal models that better recapitulate the human disease, aside from updates concerning previously established animal models, as well as new insights in the molecular mechanisms behind the disorders. This Special Issue intends to present new interesting developments in the field. Articles offering innovative insights in the multifaceted pathophysiology of neurological disorders are welcome. This Special Issue may include, but is not limited to: original research articles focusing on differential gene expression analyses of genetic models, development of new models, further characterization of established models, therapeutic studies utilizing animal models, and review articles which summarize and highlight recent advances in the field.

Prof. Dr. Changjong Moon
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • neurological disorders
  • animal models
  • developmental models
  • genetic models
  • molecular mechanisms
  • genetic analysis
  • drug efficacy testing

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Published Papers (17 papers)

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Research

Jump to: Review

19 pages, 2124 KiB  
Article
SREBP-1c Deficiency Affects Hippocampal Micromorphometry and Hippocampus-Dependent Memory Ability in Mice
by Mary Jasmin Ang, Sueun Lee, Mai Wada, Poornima D. E. Weerasinghe-Mudiyanselage, Sung-Ho Kim, Taekyun Shin, Tae-Il Jeon, Seung-Soon Im and Changjong Moon
Int. J. Mol. Sci. 2021, 22(11), 6103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116103 - 05 Jun 2021
Cited by 7 | Viewed by 3334
Abstract
Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration [...] Read more.
Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration of novel modulatory molecules in the hippocampus and occurrence of schizophrenia-like behaviors in mice. However, the possible underlying mechanisms, related to neuronal plasticity in the hippocampus, are yet to be elucidated. In this study, we investigated the hippocampus-dependent memory function and neuronal architecture of hippocampal neurons in SREBP-1c knockout (KO) mice. During the passive avoidance test, SREBP-1c KO mice showed memory impairment. Based on Golgi staining, the dendritic complexity, length, and branch points were significantly decreased in the apical cornu ammonis (CA) 1, CA3, and dentate gyrus (DG) subregions of the hippocampi of SREBP-1c KO mice, compared with those of wild-type (WT) mice. Additionally, significant decreases in the dendritic diameters were detected in the CA3 and DG subregions, and spine density was also significantly decreased in the apical CA3 subregion of the hippocampi of KO mice, compared with that of WT mice. Alterations in the proportions of stubby and thin-shaped dendritic spines were observed in the apical subcompartments of CA1 and CA3 in the hippocampi of KO mice. Furthermore, the corresponding differential decreases in the levels of SREBP-1 expression in the hippocampal subregions (particularly, a significant decrease in the level in the CA3) were detected by immunofluorescence. This study suggests that the contributions of SREBP-1c to the structural plasticity of the mouse hippocampus may have underlain the behavioral alterations. These findings offer insights into the critical role of SREBP-1c in hippocampal functioning in mice. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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28 pages, 4274 KiB  
Article
An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA
by Alon M. Douek, Mitra Amiri Khabooshan, Jason Henry, Sebastian-Alexander Stamatis, Florian Kreuder, Georg Ramm, Minna-Liisa Änkö, Donald Wlodkowic and Jan Kaslin
Int. J. Mol. Sci. 2021, 22(11), 5948; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115948 - 31 May 2021
Cited by 9 | Viewed by 5029
Abstract
Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA [...] Read more.
Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA represents a significant proportion of childhood dementias. This condition generally leads to patient death in the teenage years, yet no effective therapy exists for MPS IIIA and a complete understanding of the mechanisms of MPS IIIA pathogenesis is lacking. Here, we employ targeted CRISPR/Cas9 mutagenesis to generate a model of MPS IIIA in the zebrafish, a model organism with strong genetic tractability and amenity for high-throughput screening. The sgshΔex5−6 zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgshΔex5−6 zebrafish faithfully recapitulate diverse CNS-specific features of MPS IIIA, including neuronal lysosomal overabundance, complex behavioural phenotypes, and profound, lifelong neuroinflammation. We further demonstrate that neuroinflammation in sgshΔex5−6 zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in sgshΔex5−6 mutant larvae in a context-dependent manner. We expect the sgshΔex5−6 zebrafish mutant to be a valuable resource in gaining a better understanding of MPS IIIA pathobiology towards the development of timely and effective therapeutic interventions. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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19 pages, 9267 KiB  
Article
Exposure to RF-EMF Alters Postsynaptic Structure and Hinders Neurite Outgrowth in Developing Hippocampal Neurons of Early Postnatal Mice
by Ju Hwan Kim, Kyung Hwun Chung, Yeong Ran Hwang, Hye Ran Park, Hee Jung Kim, Hyung-Gun Kim and Hak Rim Kim
Int. J. Mol. Sci. 2021, 22(10), 5340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105340 - 19 May 2021
Cited by 11 | Viewed by 2816
Abstract
Exposure to radiofrequency electromagnetic fields (RF-EMFs) has increased rapidly in children, but information on the effects of RF-EMF exposure to the central nervous system in children is limited. In this study, pups and dams were exposed to whole-body RF-EMF at 4.0 W/kg specific [...] Read more.
Exposure to radiofrequency electromagnetic fields (RF-EMFs) has increased rapidly in children, but information on the effects of RF-EMF exposure to the central nervous system in children is limited. In this study, pups and dams were exposed to whole-body RF-EMF at 4.0 W/kg specific absorption rate (SAR) for 5 h per day for 4 weeks (from postnatal day (P) 1 to P28). The effects of RF-EMF exposure on neurons were evaluated by using both pups’ hippocampus and primary cultured hippocampal neurons. The total number of dendritic spines showed statistically significant decreases in the dentate gyrus (DG) but was not altered in the cornu ammonis (CA1) in hippocampal neurons. In particular, the number of mushroom-type dendritic spines showed statistically significant decreases in the CA1 and DG. The expression of glutamate receptors was decreased in mushroom-type dendritic spines in the CA1 and DG of hippocampal neurons following RF-EMF exposure. The expression of brain-derived neurotrophic factor (BDNF) in the CA1 and DG was significantly lower statistically in RF-EMF-exposed mice. The number of post-synaptic density protein 95 (PSD95) puncta gradually increased over time but was significantly decreased statistically at days in vitro (DIV) 5, 7, and 9 following RF-EMF exposure. Decreased BDNF expression was restricted to the soma and was not observed in neurites of hippocampal neurons following RF-EMF exposure. The length of neurite outgrowth and number of branches showed statistically significant decreases, but no changes in the soma size of hippocampal neurons were observed. Further, the memory index showed statistically significant decreases in RF-EMF-exposed mice, suggesting that decreased synaptic density following RF-EMF exposure at early developmental stages may affect memory function. Collectively, these data suggest that hindered neuronal outgrowth following RF-EMF exposure may decrease overall synaptic density during early neurite development of hippocampal neurons. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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14 pages, 3443 KiB  
Article
Amelioration of Cognitive and Behavioral Deficits after Traumatic Brain Injury in Coagulation Factor XII Deficient Mice
by Christian Stetter, Simon Lopez-Caperuchipi, Sarah Hopp-Krämer, Michael Bieber, Christoph Kleinschnitz, Anna-Leena Sirén and Christiane Albert-Weißenberger
Int. J. Mol. Sci. 2021, 22(9), 4855; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094855 - 03 May 2021
Cited by 4 | Viewed by 2553
Abstract
Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits [...] Read more.
Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII−/− mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII−/− mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII−/− mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII−/− mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII−/− mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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12 pages, 1324 KiB  
Article
Functional Dysregulations in CA1 Hippocampal Networks of a 3-Hit Mouse Model of Schizophrenia
by Solenn Percelay, Jean-Marie Billard, Thomas Freret, Annie Andrieux, Michel Boulouard and Valentine Bouet
Int. J. Mol. Sci. 2021, 22(5), 2644; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052644 - 05 Mar 2021
Cited by 7 | Viewed by 1973
Abstract
For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of [...] Read more.
For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of the MAP6 gene, early-life stress—maternal separation, and pharmacological treatment—chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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19 pages, 3556 KiB  
Article
Transcriptome Sequencing in the Preoptic Region of Rat Dams Reveals a Role of Androgen Receptor in the Control of Maternal Behavior
by András H. Lékó, Rashmi Kumari, Fanni Dóra, Dávid Keller, Edina B. Udvari, Vivien Csikós, Éva Renner and Arpád Dobolyi
Int. J. Mol. Sci. 2021, 22(4), 1517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041517 - 03 Feb 2021
Cited by 4 | Viewed by 2033
Abstract
(1) Background: Preoptic region of hypothalamus is responsible to control maternal behavior, which was hypothesized to be associated with gene expressional changes. (2) Methods: Transcriptome sequencing was first applied in the preoptic region of rat dams in comparison to a control group of [...] Read more.
(1) Background: Preoptic region of hypothalamus is responsible to control maternal behavior, which was hypothesized to be associated with gene expressional changes. (2) Methods: Transcriptome sequencing was first applied in the preoptic region of rat dams in comparison to a control group of mothers whose pups were taken away immediately after parturition and did not exhibit caring behavior 10 days later. (3) Results: Differentially expressed genes were found and validated by quantitative RT-PCR, among them NACHT and WD repeat domain containing 1 (Nwd1) is known to control androgen receptor (AR) protein levels. The distribution of Nwd1 mRNA and AR was similar in the preoptic area. Therefore, we focused on this steroid hormone receptor and found its reduced protein level in rat dams. To establish the function of AR in maternal behavior, its antagonist was administered intracerebroventricularly into mother rats and increased pup-directed behavior of the animals. (4) Conclusions: AR levels are suppressed in the preoptic area of mothers possibly mediated by altered Nwd1 expression in order to allow sustained high-level care for the pups. Thus, our study first implicated the AR in the control of maternal behaviors. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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16 pages, 1544 KiB  
Article
Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome
by Qi Ding, Fan Zhang, Yue Feng and Hongbing Wang
Int. J. Mol. Sci. 2020, 21(23), 9327; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239327 - 07 Dec 2020
Cited by 6 | Viewed by 2891
Abstract
Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, [...] Read more.
Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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16 pages, 2171 KiB  
Article
Interplay of Prenatal and Postnatal Risk Factors in the Behavioral and Histological Features of a “Two-Hit” Non-Genetic Mouse Model of Schizophrenia
by Yi-Chun Chang, Wai-Yu Li, Lukas Jyuhn-Hsiarn Lee and Li-Jen Lee
Int. J. Mol. Sci. 2020, 21(22), 8518; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228518 - 12 Nov 2020
Cited by 2 | Viewed by 2263
Abstract
Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were [...] Read more.
Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were weaned at postnatal day 28. After weaning, male offspring were randomly assigned into group-rearing and isolation-rearing groups. In their adulthood, we performed behavioral tests and characterized the histochemical features of their mesocorticolimbic structures. The sociability and anxiety levels were not affected by either manipulation, but synergistic effects of the two hits on stress-coping behavior was observed. Either of the single manipulations caused defects in sensorimotor gating, novel object recognition and spatial memory tests, but the combination of the two hits did not further exacerbate the disabilities. Prenatal infection increased the number of dopaminergic neurons in midbrain, whereas postweaning isolation decreased the GABAergic neurons in cortex. Single manipulation reduced the dendritic complexity and spine densities of neurons in the medial prefrontal cortex (mPFC) and dentate gyrus. Our results support the current perspective that disturbances in brain development during the prenatal or postnatal period influence the structure and function of the brain and together augment the susceptibility to mental disorders, such as schizophrenia. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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17 pages, 1804 KiB  
Article
Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice
by Mary Jasmin Ang, Juhwan Kim, Sueun Lee, Sung-Ho Kim, Jong-Choon Kim, Tae-Il Jeon, Seung-Soon Im and Changjong Moon
Int. J. Mol. Sci. 2020, 21(11), 4131; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114131 - 10 Jun 2020
Cited by 10 | Viewed by 3378
Abstract
Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in [...] Read more.
Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in the central nervous system. However, little is known about the biological effects of SREBP-1c in the brain. Our previous study uncovered that mice deficient in SREBP-1c exhibit schizophrenia-like behaviors. To investigate whether there are novel molecular mechanisms involved in the neurological aberrations caused by SREBP-1c deficiency, we analyzed the transcriptomes of the hippocampus of SREBP-1c knockout (KO) mice and wild-type mice. We found seven differentially expressed genes (three up-regulated and four down-regulated genes) in the hippocampus of SREBP-1c KO mice. For further verification, we selected the three most significantly changed genes: glucagon-like peptide 2 receptors (GLP2R) involved in hippocampal neurogenesis and neuroplasticity as well as in cognitive impairments; necdin (NDN) which is related to neuronal death and neurodevelopmental disorders; and Erb-B2 receptor tyrosine kinase 4 (ERBB4) which is a receptor for schizophrenia-linked protein, neuregulin-1. The protein levels of GLP2R and NDN were considerably decreased, but the level of ERBB4 was significantly increased in the hippocampus of SREBP-1c KO mice. However, further confirmation is warranted to establish the translatability of these findings from this rodent model into human patients. We suggest that these data provide novel molecular evidence for the modulatory role of SREBP-1c in the mouse hippocampus. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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Review

Jump to: Research

40 pages, 1966 KiB  
Review
Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives
by Tiziana Bonifacino, Roberta Arianna Zerbo, Matilde Balbi, Carola Torazza, Giulia Frumento, Ernesto Fedele, Giambattista Bonanno and Marco Milanese
Int. J. Mol. Sci. 2021, 22(22), 12236; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212236 - 12 Nov 2021
Cited by 39 | Viewed by 5846
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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20 pages, 1537 KiB  
Review
Epileptic Mechanisms Shared by Alzheimer’s Disease: Viewed via the Unique Lens of Genetic Epilepsy
by Jing-Qiong Kang
Int. J. Mol. Sci. 2021, 22(13), 7133; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137133 - 01 Jul 2021
Cited by 12 | Viewed by 3843
Abstract
Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer’s disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and [...] Read more.
Our recent work on genetic epilepsy (GE) has identified common mechanisms between GE and neurodegenerative diseases including Alzheimer’s disease (AD). Although both disorders are seemingly unrelated and occur at opposite ends of the age spectrum, it is likely there are shared mechanisms and studies on GE could provide unique insights into AD pathogenesis. Neurodegenerative diseases are typically late-onset disorders, but the underlying pathology may have already occurred long before the clinical symptoms emerge. Pathophysiology in the early phase of these diseases is understudied but critical for developing mechanism-based treatment. In AD, increased seizure susceptibility and silent epileptiform activity due to disrupted excitatory/inhibitory (E/I) balance has been identified much earlier than cognition deficit. Increased epileptiform activity is likely a main pathology in the early phase that directly contributes to impaired cognition. It is an enormous challenge to model the early phase of pathology with conventional AD mouse models due to the chronic disease course, let alone the complex interplay between subclinical nonconvulsive epileptiform activity, AD pathology, and cognition deficit. We have extensively studied GE, especially with gene mutations that affect the GABA pathway such as mutations in GABAA receptors and GABA transporter 1. We believe that some mouse models developed for studying GE and insights gained from GE could provide unique opportunity to understand AD. These include the pathology in early phase of AD, endoplasmic reticulum (ER) stress, and E/I imbalance as well as the contribution to cognitive deficit. In this review, we will focus on the overlapping mechanisms between GE and AD, the insights from mutations affecting GABAA receptors, and GABA transporter 1. We will detail mechanisms of E/I imbalance and the toxic epileptiform generation in AD, and the complex interplay between ER stress, impaired membrane protein trafficking, and synaptic physiology in both GE and AD. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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25 pages, 679 KiB  
Review
Tau Seeding Mouse Models with Patient Brain-Derived Aggregates
by Aiko Robert, Michael Schöll and Thomas Vogels
Int. J. Mol. Sci. 2021, 22(11), 6132; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116132 - 07 Jun 2021
Cited by 13 | Viewed by 4462
Abstract
Tauopathies are a heterogeneous class of neurodegenerative diseases characterized by intracellular inclusions of aggregated tau proteins. Tau aggregates in different tauopathies have distinct structural features and can be found in different cell types. Transgenic animal models overexpressing human tau have been used for [...] Read more.
Tauopathies are a heterogeneous class of neurodegenerative diseases characterized by intracellular inclusions of aggregated tau proteins. Tau aggregates in different tauopathies have distinct structural features and can be found in different cell types. Transgenic animal models overexpressing human tau have been used for over two decades in the research of tau pathology. However, these models poorly recapitulate the heterogeneity of tauopathies found in human brains. Recent findings demonstrate that injection of purified tau aggregates from the brains of human tauopathy patients recapitulates both the structural features and cell-type specificity of the tau pathology of the donor tauopathy. These models may therefore have unique translational value in the study of functional consequences of tau pathology, tau-based diagnostics, and tau targeting therapeutics. This review provides an update of the literature relating to seeding-based tauopathy and their potential applications. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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22 pages, 443 KiB  
Review
Where and Why Modeling Amyotrophic Lateral Sclerosis
by Francesco Liguori, Susanna Amadio and Cinzia Volonté
Int. J. Mol. Sci. 2021, 22(8), 3977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083977 - 12 Apr 2021
Cited by 20 | Viewed by 3793
Abstract
Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates [...] Read more.
Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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16 pages, 2196 KiB  
Review
Experimental Model Systems for Understanding Human Axonal Injury Responses
by Bohm Lee and Yongcheol Cho
Int. J. Mol. Sci. 2021, 22(2), 474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020474 - 06 Jan 2021
Cited by 4 | Viewed by 3536
Abstract
Neurons are structurally unique and have dendrites and axons that are vulnerable to injury. Some neurons in the peripheral nervous system (PNS) can regenerate their axons after injuries. However, most neurons in the central nervous system (CNS) fail to do so, resulting in [...] Read more.
Neurons are structurally unique and have dendrites and axons that are vulnerable to injury. Some neurons in the peripheral nervous system (PNS) can regenerate their axons after injuries. However, most neurons in the central nervous system (CNS) fail to do so, resulting in irreversible neurological disorders. To understand the mechanisms of axon regeneration, various experimental models have been utilized in vivo and in vitro. Here, we collate the key experimental models that revealed the important mechanisms regulating axon regeneration and degeneration in different systems. We also discuss the advantages of experimenting with the rodent model, considering the application of these findings in understanding human diseases and for developing therapeutic methods. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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24 pages, 4707 KiB  
Review
Peripheral Nerve Regeneration and Muscle Reinnervation
by Tessa Gordon
Int. J. Mol. Sci. 2020, 21(22), 8652; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228652 - 17 Nov 2020
Cited by 146 | Viewed by 12216
Abstract
Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The [...] Read more.
Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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17 pages, 759 KiB  
Review
Stem Cell-Based Therapies for Parkinson Disease
by Zhaohui Liu and Hoi-Hung Cheung
Int. J. Mol. Sci. 2020, 21(21), 8060; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218060 - 29 Oct 2020
Cited by 39 | Viewed by 8761
Abstract
Parkinson disease (PD) is a neurological movement disorder resulting primarily from damage to and degeneration of the nigrostriatal dopaminergic pathway. The pathway consists of neural populations in the substantia nigra that project to the striatum of the brain where they release dopamine. Diagnosis [...] Read more.
Parkinson disease (PD) is a neurological movement disorder resulting primarily from damage to and degeneration of the nigrostriatal dopaminergic pathway. The pathway consists of neural populations in the substantia nigra that project to the striatum of the brain where they release dopamine. Diagnosis of PD is based on the presence of impaired motor features such as asymmetric or unilateral resting tremor, bradykinesia, and rigidity. Nonmotor features including cognitive impairment, sleep disorders, and autonomic dysfunction are also present. No cure for PD has been discovered, and treatment strategies focus on symptomatic management through restoration of dopaminergic activity. However, proposed cell replacement therapies are promising because midbrain dopaminergic neurons have been shown to restore dopaminergic neurotransmission and functionally rescue the dopamine-depleted striatum. In this review, we summarize our current understanding of the molecular pathogenesis of neurodegeneration in PD and discuss the development of new therapeutic strategies that have led to the initiation of exploratory clinical trials. We focus on the applications of stem cells for the treatment of PD and discuss how stem cell research has contributed to an understanding of PD, predicted the efficacy of novel neuroprotective therapeutics, and highlighted what we believe to be the critical areas for future research. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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15 pages, 653 KiB  
Review
Effects of Ketamine on Rodent Fear Memory
by Kwang H. Choi, Rina Y. Berman, Michael Zhang, Haley F. Spencer and Kennett D. Radford
Int. J. Mol. Sci. 2020, 21(19), 7173; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197173 - 28 Sep 2020
Cited by 13 | Viewed by 3732
Abstract
Ketamine, a multimodal anesthetic drug, has become increasingly popular in the treatment of pain following traumatic injury as well as treatment-resistant major depressive disorders. However, the psychological impact of this dissociative medication on the development of stress-related disorders such as post-traumatic stress disorder [...] Read more.
Ketamine, a multimodal anesthetic drug, has become increasingly popular in the treatment of pain following traumatic injury as well as treatment-resistant major depressive disorders. However, the psychological impact of this dissociative medication on the development of stress-related disorders such as post-traumatic stress disorder (PTSD) remains controversial. To address these concerns, preclinical studies have investigated the effects of ketamine administration on fear memory and stress-related behaviors in laboratory animals. Despite a well-documented line of research examining the effects of ketamine on fear memory, there is a lack of literature reviews on this important topic. Therefore, this review article summarizes the current preclinical literature on ketamine and fear memory with a particular emphasis on the route, dose, and timing of ketamine administration in rodent fear conditioning studies. Additionally, this review describes the molecular mechanisms by which ketamine may impact fear memory and stress-related behaviors. Overall, findings from previous studies are inconsistent in that fear memory may be increased, decreased, or unaltered following ketamine administration in rodents. These conflicting results can be explained by factors such as the route, dose, and timing of ketamine administration; the interaction between ketamine and stress; and individual variability in the rodent response to ketamine. This review also recommends that future preclinical studies utilize a clinically relevant route of administration and account for biological sex differences to improve translation between preclinical and clinical investigations. Full article
(This article belongs to the Special Issue Modeling Neurological Disorders in Experimental Animals: New Insights and Emerging Roles)
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